Abstract:The DR5-DQ7/DR7-DQ2 genotype is very frequent among patients affected by celiac disease (CD), in Europe. This genotype, associated to high risk of CD, carries the HLA-DQA1*05 and HLA-DQB1*02 predisposing alleles, in trans configuration. The alleles encode the DQ2.5 heterodimer responsible of gluten peptide presentation on the surface of antigen-presenting cells (APCs), and consequent pathogenic CD4+ T cell activation. We demonstrated that DR5/DR7 APCs induce an anti-gluten CD4+ T cell response, of comparable i… Show more
“…These results support already published data and confirm the different expression of CD predisposing alleles as compared to the non-predisposing ones [ 5 , 6 ].…”
Section: Resultssupporting
confidence: 92%
“…Our previous papers [ 6 , 19 ] and other previously published data [ 20 , 21 ] widely demonstrated the differential expression of HLA haplotypes associated with autoimmune diseases. Many polymorphisms are identified in the intergenic regions that affect the binding of transcription factors or the levels of histone H3K27 acetylation.…”
Section: Discussionmentioning
confidence: 99%
“…We have previously demonstrated the differential expression of CD-associated HLA class II risk alleles in respect to non-CD associated ones in heterozygous B-LCLs. Specifically, DQA1*05:01 and DQB1*02:01 predisposing alleles and encoding DQ2.5 molecules are expressed at high levels when carried either in cis (DR3 haplotype) [ 5 ] or trans (DR5 and DR7 haplotypes) [ 6 ] configurations. This great expression influences the strength of gliadin-specific CD4 + T cells response.…”
Macrophages play an important role in the pathogenesis of celiac disease (CD) because they are involved in both inflammatory reaction and antigen presentation. We analyzed the expression of CD-associated HLA-DQ2.5 risk alleles on macrophages isolated by two cohorts of adult patients, from the U.S. and Italy, at different stages of disease and with different genotypes. After isolating and differentiating macrophages from PBMC, we assessed the HLA genotype and quantified the HLA-DQ2.5 mRNAs by qPCR, before and after gliadin stimulation. The results confirmed the differences in expression between DQA1*05:01 and DQB1*02:01 predisposing alleles and the non-CD associated alleles, as previously shown on other types of APCs. The gliadin challenge confirmed the differentiation of macrophages toward a proinflammatory phenotype, but above all, it triggered an increase of DQA1*05:01 mRNA, as well as a decrease of the DQB1*02:01 transcript. Furthermore, we observed a decrease in the DRB1 genes expression and a downregulation of the CIITA transactivator. In conclusion, our findings provide new evidences on the non-coordinated regulation of celiac disease DQ2.5 risk genes and support the hypothesis that gliadin could interfere in the three-dimensional arrangement of chromatin at the HLA locus.
“…These results support already published data and confirm the different expression of CD predisposing alleles as compared to the non-predisposing ones [ 5 , 6 ].…”
Section: Resultssupporting
confidence: 92%
“…Our previous papers [ 6 , 19 ] and other previously published data [ 20 , 21 ] widely demonstrated the differential expression of HLA haplotypes associated with autoimmune diseases. Many polymorphisms are identified in the intergenic regions that affect the binding of transcription factors or the levels of histone H3K27 acetylation.…”
Section: Discussionmentioning
confidence: 99%
“…We have previously demonstrated the differential expression of CD-associated HLA class II risk alleles in respect to non-CD associated ones in heterozygous B-LCLs. Specifically, DQA1*05:01 and DQB1*02:01 predisposing alleles and encoding DQ2.5 molecules are expressed at high levels when carried either in cis (DR3 haplotype) [ 5 ] or trans (DR5 and DR7 haplotypes) [ 6 ] configurations. This great expression influences the strength of gliadin-specific CD4 + T cells response.…”
Macrophages play an important role in the pathogenesis of celiac disease (CD) because they are involved in both inflammatory reaction and antigen presentation. We analyzed the expression of CD-associated HLA-DQ2.5 risk alleles on macrophages isolated by two cohorts of adult patients, from the U.S. and Italy, at different stages of disease and with different genotypes. After isolating and differentiating macrophages from PBMC, we assessed the HLA genotype and quantified the HLA-DQ2.5 mRNAs by qPCR, before and after gliadin stimulation. The results confirmed the differences in expression between DQA1*05:01 and DQB1*02:01 predisposing alleles and the non-CD associated alleles, as previously shown on other types of APCs. The gliadin challenge confirmed the differentiation of macrophages toward a proinflammatory phenotype, but above all, it triggered an increase of DQA1*05:01 mRNA, as well as a decrease of the DQB1*02:01 transcript. Furthermore, we observed a decrease in the DRB1 genes expression and a downregulation of the CIITA transactivator. In conclusion, our findings provide new evidences on the non-coordinated regulation of celiac disease DQ2.5 risk genes and support the hypothesis that gliadin could interfere in the three-dimensional arrangement of chromatin at the HLA locus.
“…Similarly, the percentage of CD-associated DQB1*02 mRNA ranged from 85 % to 99 % compared to DQB1*03 and DQB1*05 mRNAs, not associated with the disease, that fluctuated from 1 % to 15 %. Our results confirmed the greatest expression of DQA1*05 and DQB1*02 risk alleles in PBMCs in all groups of heterozygous genotypes analyzed, as already demonstrated in B cells [ 10 , 14 ]. Fig.…”
“…Elevated HLA expression levels have been associated with inflammatory bowel diseases ( 56 , 76 ), scleroderma patients with interstitial lung disease ( 77 ), ankylosing spondylitis ( 78 ), Graves’ disease ( 79 ), systemic lupus erythematosus ( 80 ), rheumatoid arthritis ( 72 ), and multiple sclerosis ( 81 ). Additionally, in celiac disease and type 1 diabetes, higher expression of DQA1*05 and DQB1*02 alleles was found in patients when compared to healthy controls ( 82 , 83 ). There is evidence that also low HLA expression predisposes to diseases.…”
Section: Hla Expression In Human Diseasesmentioning
Varying HLA allele-specific expression levels are associated with human diseases, such as graft versus host disease (GvHD) in hematopoietic stem cell transplantation (HSCT), cytotoxic T cell response and viral load in HIV infection, and the risk of Crohn’s disease. Only recently, RNA-based next generation sequencing (NGS) methodologies with accompanying bioinformatics tools have emerged to quantify HLA allele-specific expression replacing the quantitative PCR (qPCR) -based methods. These novel NGS approaches enable the systematic analysis of the HLA allele-specific expression changes between individuals and between normal and disease phenotypes. Additionally, analyzing HLA allele-specific expression and allele-specific expression loss provide important information for predicting efficacies of novel immune cell therapies. Here, we review available RNA sequencing-based approaches and computational tools for NGS to quantify HLA allele-specific expression. Moreover, we explore recent studies reporting disease associations with differential HLA expression. Finally, we discuss the role of allele-specific expression in HSCT and how considering the expression quantification in recipient-donor matching could improve the outcome of HSCT.
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